The selection of targeted therapies for relapsed or refractory advanced renal cell carcinoma.

Introduction: Advancements in immunotherapy and angiogenesis-targeted therapies have transformed the upfront treatment of renal cell carcinoma (RCC). However, long-term prognoses for patients with unresectable and metastatic disease often remain limited, with the majority experiencing progression after exposure to front-line therapy. In most cases of relapsed or refractory (R/R) disease after prior exposure to an immune checkpoint inhibitor (ICI), there is no role for ICI-rechallenge. Therefore, treatment of R/R RCC relies on the appropriate selection of therapies targeting growth pathways dependent on vascular endothelial growth factor (VEGF) or hypoxia-inducible factor (HIF).

Areas covered: This review article summarizes the current landscape of targeted therapies for use in second-line or later-line settings for the treatment of clear cell and non-clear cell RCC. Novel therapeutic strategies currently in development are also discussed.

Expert opinion: The treatment of R/R RCC primarily consists of inhibition of VEGF, HIF, and mTOR pathways, and the selection of a specific agent depends on the histologic subtype of the tumor, the prior lines of therapy chosen, and patient co-morbidities. Future tumor-based and circulating biomarker research might one day enable the identification of transcriptional signatures that could predict a response to immune, angiogenesis, or HIF-based therapies.